Wu Tiyun, Hou Haitong, Dey Anup, Bachu Mahesh, Chen Xiongfong, Wisniewski Jan, Kudoh Fuki, Chen Chao, Chauhan Sakshi, Xiao Hua, Pan Richard, Ozato Keiko
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China.
iScience. 2024 Apr 30;27(7):109797. doi: 10.1016/j.isci.2024.109797. eCollection 2024 Jul 19.
Bromodomain protein BRD4 binds to acetylated histones to regulate transcription. BRD4 also drives cancer cell proliferation. However, the role of BRD4 in normal cell growth has remained unclear. Here, we investigated this question by using mouse embryonic fibroblasts with conditional Brd4 knockout (KO). We found that Brd4KO cells grow more slowly than wild type cells; they do not complete replication, fail to achieve mitosis, and exhibit extensive DNA damage throughout all cell cycle stages. BRD4 was required for expression of more than 450 cell cycle genes including genes encoding core histones and centromere/kinetochore proteins that are critical for genome replication and chromosomal segregation. Moreover, we show that many genes controlling R-loop formation and DNA damage response (DDR) require BRD4 for expression. Finally, BRD4 constitutively occupied genes controlling R-loop, DDR and cell cycle progression. In summary, BRD4 epigenetically marks above genes and serves as a master regulator of normal cell growth.
溴结构域蛋白BRD4与乙酰化组蛋白结合以调节转录。BRD4还驱动癌细胞增殖。然而，BRD4在正常细胞生长中的作用仍不清楚。在此，我们通过使用条件性Brd4基因敲除（KO）的小鼠胚胎成纤维细胞来研究这个问题。我们发现Brd4KO细胞比野生型细胞生长得更慢；它们无法完成复制，不能进入有丝分裂，并且在所有细胞周期阶段都表现出广泛的DNA损伤。BRD4是450多个细胞周期基因表达所必需的，这些基因包括编码对基因组复制和染色体分离至关重要的核心组蛋白和着丝粒/动粒蛋白的基因。此外，我们表明许多控制R环形成和DNA损伤反应（DDR）的基因需要BRD4来表达。最后，BRD4持续占据控制R环、DDR和细胞周期进程的基因。总之，BRD4在上述基因上进行表观遗传标记，并作为正常细胞生长的主要调节因子。
